In radiopharmacy, technetium 99m is obtained as an aqueous solution of sodium pertechnetate, where Tc has the oxidation state +VII. Several reducing agents have been employed to reduce the pertechnetate to a lower oxidation state. The stannous ion in the form of a water soluble salt is the most commonly used agent, particularly as the stannous chloride.
In the reduced form, Tc forms cations which are complexed with a number of complexing agents, such as diethylene triamine pentacetic acid, methylenediphosphonic acid, and imino diacetic acids. The Tc II to Tc V cations are hydrated oxo ions, and in this oxidation state ions are generally referred to in the radiopharmaceutical literature as "reduced pertechnetate-Tc99m".
The use of substituted iminodiacetic acids and substituted imino diacetic acids complexed with a form of technetium 99m and stannous ion are disclosed to be useful as agents for imaging the hepatobiliary system by Loberg et al. in U.S. Pat. No. 4,017,596. Other related compounds are reported by Subramanian J. Nucl. Med. 18, 624 (1977). These compounds are substituted nitrilotriacetic acid mono amides. Other substituted iminodiacetic acids are disclosed in U.K. Patent specification No. 1,545,437 as useful in diagnosing hepatobiliary function using complexes with technetium 99m; in U.K. patent specification No. 1,308,793 as useful chelating agents. Other iminodiacetic acids useful as chelating agents with technetium 99m are disclosed as follows:
______________________________________ 1. Radiopharmaceuticals II p 587, 592 2. Journal of Nuclear Medicine 17, 633-8 (1976) 3. Journal of Nuclear Medicine 18, 624 (1977) 4. Journal of Nuclear Medicine 18, 455 (1977) 5. Journal of Nuclear Medicine 18, 997 (1977) 6. Radiology 128, 793 (1978) 7. European Journal of 4, 445 (1979) Nuclear Medicine 8. Journal of Pharmaceutical 68, 317 (1979) Sciences 9. Journal of Pharmaceutical 69, 731 (1980) Sciences ______________________________________
It is known from these publications that chelates of certain of the above noted substituted iminodiacetic acids with technetium 99m are excreted through both the urine and the biliary ducts. One of the drawbacks of using these prior art compounds in visualizing the hepatobiliary system is that in the case of liver disease the visualization of the hepatobiliary system is unsatisfactory. This is believed to be true because of improper functioning of the biliary ducts in which case excretion of the compounds is accomodated by way of the urine.
Substituted iminodiacetic acids, as defined hereinabove, are capable of forming molecular complexes with technetium 99m in the reduced form. These radiolabelled biological agents have a high degree of in vivo stability and are highly selective for the hepatobiliary system.
It is an object of the invention to provide such complexes useful in diagnosing hepatobiliary function in the presence of liver disease. It is a further object of the invention to provide a novel diagnostic kit for hepatobiliary imaging comprising a freeze-dried mixture of a soluble stannous salt and a novel iminodiacetic acid of the formula given above. A still further object of the present invention is to provide a process for the preparation of said compounds by reaction of nitrilotriacetic acid anhydride and an amine of the formula R.sup.1 NH.sub.2 wherein R.sup.1 is as defined above.